US4647568A - Circulation-active hydroxy-tetra-hydropyridinelactones - Google Patents

Circulation-active hydroxy-tetra-hydropyridinelactones Download PDF

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Publication number
US4647568A
US4647568A US06/673,296 US67329684A US4647568A US 4647568 A US4647568 A US 4647568A US 67329684 A US67329684 A US 67329684A US 4647568 A US4647568 A US 4647568A
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United States
Prior art keywords
methyl
atoms
chain
alkyl
oxo
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US06/673,296
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Inventor
Klaus Gorlitzer
Ulrich Bartke
Siegfried Goldmann
Matthias Schramm
Gunter Thomas
Rainer Gross
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Bayer AG
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Bayer AG
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Assigned to BAYER AKIENGESELLSCHAFT reassignment BAYER AKIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: BARTKE, ULRICH, GOLDMANN, SIEGFRIED, GORLITZER, KLAUS, GROSS, RAINER, SCHRAMM, MATTHIAS, THOMAS, GUNTER
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to new 2-hydroxy-1,2,3,4-tetrahydropyridinelactones, i.e., hexahydrofuro-[3,4-b]pyridine derivatives, a process for their preparation and their use in medicaments, in particular in medicaments which influence the circulation.
  • the new compounds are characterized by the following formula (I): ##STR2## in which R represents a phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl, quinoxalyl, thionaphthenyl, isothionaphthenyl, chromonyl, thiochromonyl, chromenyl, thiochromenyl, benzoxadiazolyl or benzthiadiazolyl radical, and the stated radicals can, if appropriate, contain 1 to 3 identical or different substituents from the group comprising alkyl (1 to 20 carbon atoms), alkenyl
  • R 1 represents a straight-chain, branched or cyclic saturated or unsaturated hydrocabon radical (1 to 20 C atoms) which can, if appropriate, be interrupted in the chain by 1 or 2 oxygen or sulphur atoms and can be optionally substituted by one or more fluorine atoms, NO 2 , trialkylsilyl (3 to 12 C atoms), hydroxyl, chlorine, bromine, iodine or cyano,
  • R 2 represents hydrogen, --NH 2 , --CHO, cyano, --CH 2 OH or a straight-chain or branched saturated or unsaturated hydrocarbon radical (1 to 8 C atoms) and
  • R 3 represents hydrogen or a straight-chain or branched alkyl radical (1 to 10 C atoms) which is, if appropriate, interrupted in the alkyl chain by one or two oxygen atoms and can be optionally substituted by fluorine, chlorine, bromine, iodine, --CN, --NH 2 , --OH or morpholino,
  • R represents a phenyl, naphthyl, thienyl, pyrryl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl, thionaphthenyl, chromonyl, thiochromonyl, chromenyl, thiochromenyl, benzoxadiazolyl or benzthiadiazolyl radical, and the stated radical can, if appropriate, contain 1 to 3 identical or different substituents from the group comprising alkyl (1 to 15 carbon atoms), alkenyl (2 to 15 carbon atoms), alkinyl (2 to 15 C atoms), alkoxy (1 to 15 C atoms), fluorine, chlorine, bromine, iodine, trifluoromethyl, monofluoro
  • R 1 represents a straight-chain, branched or cyclic saturated or unsaturated hydrocarbon radical (1 to 15 C atoms) which can, if appropriate, be interrupted in the chain by 1 or 2 oxygen or sulphur atoms and can be optionally substituted by one or more fluorine atoms, NO 2 , trialkylsilyl (3 to 9 C atoms), hydroxyl, chlorine, or cyano,
  • R 2 represents hydrogen, --CHO, --cyano or a straight-chain or branched saturated or unsaturated hydrocarbon radical (1 to 6 C atoms) and
  • R 3 represents hydrogen or a straight-chain or branched alkyl radical (1 to 6 C atoms) which is, if appropriate, interrupted in the alkyl chain by one or two oxygen atoms and can be optionally substituted by fluorine, chlorine, cyano, hydroxyl or morpholino.
  • R 1 represents a straight-chain or branched alkyl radical (1 to 5 C atoms) which can, if appropriate, be interrupted in the chain by an oxygen or sulphur atom and can be optionally substituted by one or more fluorine atoms, or trialkylsilyl (3 to 6 C atoms),
  • R 2 represents hydrogen or a straight-chain or branched alkyl radical (1 to 4 C atoms), and
  • R 3 represents hydrogen or a straight-chain or branched alkyl radical (1 to 4 C atoms) which is, if appropriate, interrupted in the alkyl chain by an oxygen atom and can be optionally substituted by morpholino.
  • R 1 , R 2 and R 3 have the meanings given above, if appropriate in the presence of inert organic solvents at temperatures between 0° and 150°.
  • the reactants can be used in any desired ratios; equimolar amounts are preferably used, but (III) can be employed in up to five-fold excess.
  • the reaction temperature is preferably 20° to 60° C. when the reaction is carried out in the presence of inert solvents, and 40° to 140° C. when the reaction is carried out without solvents.
  • Suitable solvents are all inert solvents, such as, for example, alcohols, preferably tert.-butanol, or aromatics, such as toluene or benzene.
  • Benzylidene compounds (II) used for the preparation are known and can be prepared by known processes (J. Org. Chem. 43, 1541 (1978) and Z. Chem. 10, 341 (1970)).
  • Aminocrotonates (III) used as starting materials are known and can be prepared by known processes (Cope, J. Amer. Chem. Soc. 67, 1017 (1945)).
  • Suitable solvents for converting (I) to (IV) are all inert solvents, such as, for example, alcohols, for example ethanol, aromatics, such as toluene, or esters, such as ethyl acetate.
  • Suitable catalysts are all mineral acids, such as, for example, hydrochloric acid or sulphuric acid.
  • the reaction temperature is -30° to the boiling point of the solvent, preferably 0° to +50° C.
  • the compounds according to the invention exhibit a valuable pharmacological action spectrum. They can be used as cardiotonics for improving the contractility of the heart. Moreover, they increase the flow of Ca ++ into the cells and therefore be employed as antihypotonics, for lowering the blood sugar level, for reducing the swelling of mucous membranes and for influencing the salt balance and/or fluid balance.
  • the compounds according to the invention can be converted in a known manner to the customary formulations, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, that is to say in amounts which suffice to achieve the stated dosage range.
  • the formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, optionally with the use of emulsifiers and/or dispersing agents, and, for example when using water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • auxiliary substances which may be mentioned are: water, non-toxic organic solvents, such as paraffins (for example petroleum fractions), vegetable oils (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol), glycols (for example propylene glycol and polyethylene glycol), solid excipients, such as, for example, natural rock powders (for example kaolins, aluminas, talc chalk), synthetic rock powders (for example highly disperse silica and silicates), sugars (for example cane sugar, lactose and glucose), emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulphonates and arylsulphonates), dispersing agents (for example lignin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid
  • the tablets can, of course, also contain, in addition to the excipients mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances, such as starch, preferably potato starch, gelatine and the like. Furthermore, lubricants, such as magnesium stearate, sodium lauryl-sulphate and talc, can be concomitantly used when making tablets.
  • the active compounds can be mixed with various flavor-improving agents or colorants in addition to the abovementioned auxiliary substances.
  • Ethyl 7a-hydroxy-2-methyl-4-(3-nitrophenyl)-5-oxo-1,4,4a,5,7,7a-hexahydrofuro[3,4-b]pyridine-3-carboxylate is dissolved in toluene, catalytic amounts of p-toluenesulphonic acid are added, the mixture is warmed for a short time and extracted by shaking with Na 2 CO 3 solution, and the organic phase is dried and evaporated down. M.p.: 229° C.
US06/673,296 1983-12-02 1984-11-20 Circulation-active hydroxy-tetra-hydropyridinelactones Expired - Fee Related US4647568A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19833343658 DE3343658A1 (de) 1983-12-02 1983-12-02 Hydroxy-tetrahydropyridinlactone, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
DE3343658 1983-12-02

Publications (1)

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US4647568A true US4647568A (en) 1987-03-03

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US (1) US4647568A (de)
EP (1) EP0144847A3 (de)
JP (1) JPS60132988A (de)
DE (1) DE3343658A1 (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4721719A (en) * 1986-01-17 1988-01-26 Bayer Aktiengesellschaft Dihydropyridinelactols and their use as medicaments which influence blood sugar
US4801715A (en) * 1985-12-18 1989-01-31 Bayer Aktiengesellschaft Certain 4-thienyl-dihydropyridines
US20050203119A1 (en) * 2003-09-10 2005-09-15 Mitsunori Ono Dihydropyridine compounds for treating or preventing metabolic disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145432A (en) * 1975-07-02 1979-03-20 Fujisawa Pharmaceutical Co., Ltd. 6-acyloryalkyl-1,4-dihydropyridine derivatives and a method of effecting vasodilation therewith
US4211872A (en) * 1978-12-11 1980-07-08 Hung William M Substituted furopyridinones and furopyrazinones
US4532248A (en) * 1981-07-30 1985-07-30 Bayer Aktiengesellschaft Method of combatting coronary and vascular diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145432A (en) * 1975-07-02 1979-03-20 Fujisawa Pharmaceutical Co., Ltd. 6-acyloryalkyl-1,4-dihydropyridine derivatives and a method of effecting vasodilation therewith
US4211872A (en) * 1978-12-11 1980-07-08 Hung William M Substituted furopyridinones and furopyrazinones
US4532248A (en) * 1981-07-30 1985-07-30 Bayer Aktiengesellschaft Method of combatting coronary and vascular diseases

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801715A (en) * 1985-12-18 1989-01-31 Bayer Aktiengesellschaft Certain 4-thienyl-dihydropyridines
US4894378A (en) * 1985-12-18 1990-01-16 Bayer Aktiengesellschaft Lowering blood sugar with novel 4-thienyl-dihydropyridines
US4721719A (en) * 1986-01-17 1988-01-26 Bayer Aktiengesellschaft Dihydropyridinelactols and their use as medicaments which influence blood sugar
US20050203119A1 (en) * 2003-09-10 2005-09-15 Mitsunori Ono Dihydropyridine compounds for treating or preventing metabolic disorders

Also Published As

Publication number Publication date
JPS60132988A (ja) 1985-07-16
EP0144847A2 (de) 1985-06-19
EP0144847A3 (de) 1986-04-09
DE3343658A1 (de) 1985-06-13

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